# Democratizing CAR T cell therapy by in situ programming of virus-specific T cells

> **NIH NIH K99** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $110,905

## Abstract

Engineered T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against
hematological malignancies. However, broad implementation of CAR T cell therapies is limited by the lengthy
(3–5 weeks) and costly ($350K–450K per treatment) ex vivo manufacturing pipeline. This proposal seeks to
develop antigen-presenting nanoparticles (APNs) for in situ programming of virus-specific T cells for rapid and
cost-efficient CAR T cell manufacturing. Virus-specific T cells present a promising opportunity to enhance CAR
T cell therapy, as they have improved persistence and proliferation potential, and allow for viral vaccination to
augment CAR therapy through their endogenous receptors. This proposal will focus on influenza A virus (IAV)-
specific T cells to exploit the existing seasonal influenza vaccination to boost CAR activities. To deliver CAR to
IAV-specific T cells, APNs will comprise lipid nanoparticles (LNPs) that encapsulate CAR-encoded mRNA and
are decorated with HLA-A peptide-major histocompatibility complex (pMHC) displaying influenza peptide
epitopes. This proposal will use APNs to deliver human B-cell maturation antigen (BCMA) CAR in the context of
multiple myeloma with future goals to expand to other CAR specificities and indications, including CD19 positive
cancers. The goal in Aim 1 is to develop APNs for transfection of human influenza-specific T cells with αBCMA
CAR in vivo, and characterize the CAR transfection specificity in the target IAV-specific T cells versus other
major cell populations. Aim 2 will be focused on validating the anti-cancer efficacy of αBCMA CAR T cells after
in situ transfection using a mouse model recapitulating human multiple myeloma. The vaccination strategy to
expand IAV-specific T cells and to boost their effector functions will be tested using inactivated influenza virions
to vaccinate the CAR-expressing, IAV-specific T cells and compare the resulting anti-cancer potency with the
unvaccinated cohort. In Aim 3, CRISPR/Cas9 will be implemented with APNs for in vivo gene editing of T cells
with CAR for durable CAR expression and enhanced anti-cancer potency by delaying T-cell differentiation and
exhaustion. The success of this proposal will challenge existing paradigms of T cell engineering, reduce the cost
of CAR T cell therapy, and enhance anti-cancer activity through influenza vaccination to ultimately democratize
CAR T cells for cancer therapy. Through this work, the candidate will close the knowledge gaps by the
mentorship of an exceptional advisory committee: (1) Gabe Kwong, Ph.D. (CAR T cell engineering), (2) Phil
Santangelo, Ph.D. (mRNA therapeutics and CRISPR/Cas), (3) Rafi Ahmed, Ph.D. (anti-viral T cell immunity and
memory/exhaustion T cell biology), and (4) Madhav Dhodapkar, M.D. (hematology/oncology and myeloma
cancer models). This strong mentoring team and the abundant resources provided by Georgia Tech and Emory
University constitute a fertile mentoring environment for at...

## Key facts

- **NIH application ID:** 10739646
- **Project number:** 1K99CA276890-01A1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Fang-Yi Su
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $110,905
- **Award type:** 1
- **Project period:** 2023-09-08 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10739646

## Citation

> US National Institutes of Health, RePORTER application 10739646, Democratizing CAR T cell therapy by in situ programming of virus-specific T cells (1K99CA276890-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10739646. Licensed CC0.

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